Pain Treatment in the Companion Canine Model to Validate Rodent Results and Incentivize the Transition to Human Clinical Trials

Abstract

One of the biggest challenges for analgesic drug development is how to decide if a potential analgesic candidate will work in humans. What preclinical data are the most convincing, incentivizing and most predictive of success? Such a predicament is not unique to analgesics, and the pain field has certain advantages over drug development efforts in areas like neuropsychiatry where the etiological origins are either unknown or difficult to ascertain. For pain, the origin of the problem frequently is known, and the causative peripheral tissue insult might be observable. The main conundrum centers around evaluation of translational cell- and rodent-based results. While cell and rodent models are undeniably important first steps for screening, probing mechanism of action, and understanding factors of adsorption, distribution metabolism and excretion, two questions arise from such studies. First, are they reliable indicators of analgesic performance of a candidate drug in human acute and chronic pain? Second, what additional model systems might be capable of increasing translational confidence? We address this second question by assessing, primarily, the companion canine model, which can provide particularly strong predictive information for candidate analgesic agents in humans. This statement is mainly derived from our studies with resiniferatoxin (RTX) a potent TRPV1 agonist but also from protein therapeutics using a conjugate of Substance P and saporin. Our experience, to date, is that rodent models might be very well suited for acute pain translation, but companion canine models, and other large animal studies, can augment initial discovery research using rodent models for neuropathic or chronic pain. The larger animal models also provide strong translational predictive capacity for analgesic performance in humans, better predict dosing parameters for human trials and provide insight into behavior changes (bladder, bowel, mood, etc.) that are not readily assessed in laboratory animals. They are, however, not without problems that can be encountered with any experimental drug treatment or clinical trial. It also is important to recognize that pain treatment is a major veterinary concern and is an intrinsically worthwhile endeavor for animals as well as humans.

Syntaxin1A overexpression and pain insensitivity in individuals with 7q11.23 duplication syndrome

“…Furthermore, animal and human studies showed that TRPV1 + neurons generate nociceptive signals from many tissue damage conditions, including noxious heat, cancer, osteoarthritis, surgical incision, inflammation, and other stimuli. Conversely, blocking TRPV1 + neuronal activity using the highly potent TRPV1 agonist resiniferatoxin produces a wide range of analgesic actions that parallel the range of insensitivity seen in individuals with Dup7 ( 1 , 20 , 22 , 36 , 37 ). Thus, the TRPV1 + neurons fulfill the operative mechanisms of wide distribution in the body, responsiveness to multiple types of nociceptive stimuli as seen in people with Dup7, and analgesia upon effective inhibition.…”

Cutaneous Injection of Resiniferatoxin Completely Alleviates and Prevents Nerve-Injury-Induced Neuropathic Pain

“…The analgesic action of RTX against thermal hypersensitivity correlates well with the reduction in heat receptor TRPV1 [ 8 , 9 , 20 ]. In addition, as we have previously suggested [ 11 ], the reversal of the mechanical hypersensitivity after RTX treatment might be due to its effects on the reduction of CGRP, IB4, SP, as well as somatostatin and other ion channel levels in the primary afferent neurons that are colocalized with TRPV1 neurons and that are known to be involved in the transmission of peripheral nociception.…”

“…This is supported by the localization of TRPV1 in the small–medium sized neurons in the DRG and its distribution in the superficial layers (laminae I–II) of the dorsal horn of the spinal cord [ 11 , 13 , 15 , 58 , 59 ], and on the nerve fibers as well as on the cutaneous nerves [ 44 , 49 ], our unpublished observation. Different routes of administration of capsaicin and RTX, including oral, intrathecal, intracisternal, perineural, ganglionic, intraarticular, intraplantar and nasal, have been used to investigate and treat acute and chronic pain in animals and humans due to nerve injury, inflammation, cancer and osteoarthritis [ 20 , 21 , 22 ]. One main advantage of using peripheral and topical application is to avoid potential therapeutic issues and general side effects.…”

“…The topical application of capsaicin to the skin initially induces a burning pain sensation, followed by prolonged attenuation of the pre-existing pain from the same region [ 17 , 18 , 19 ]. Therefore, capsaicin and RTX have been widely used as a tool for treating pain in both clinical and preclinical studies [ 20 , 21 , 22 ].…”

Cell Therapy in Veterinary Medicine as a Proof-of-Concept for Human Therapies: Perspectives From the North American Veterinary Regenerative Medicine Association

“…This in turn highlights an important caveat with regards to the One Health approach in that one cell type working in one animal species may not be directly translated to a similar human type or a human condition. While all model systems have inherent limitations, the incorporation of naturally occurring disease in veterinary species along with traditional pre-clinical animal models of disease into a novel translational bio-medical research paradigm, may increase the predictive value of such data and its applicability to human medicine ( 44 , 45 ).…”